Intranasal immunization with coxsackievirus A16 virus-like particles confers protection against lethal infection in neonatal mice
Coxsackievirus A16 (CV-A16) is one of the main causative agents of hand, foot and mouth disease (HFMD) in young children and has become prevalent in the Asia-Pacific region in recent years. However, no approved vaccines or drugs are available for CV-A16 infection. CV-A16 virus-like particles (VLPs) are a potential vaccine candidate; however, whether the intranasal route of immunization is suitable for inducing immune responses against CV-A16 infection has not been clarified. In this study, the comprehensive immunogenicity and protective efficacy of the CV-A16 VLP vaccine were evaluated by multiple methods in a mouse model. In mice, a high neutralizing antibody (NTAb) titre could be elicited by intranasal immunization with CV-A16 VLPs, which produced NTAb levels similar to those induced by intranasal immunization with inactivated CV-A16. Passive immunity with NTAbs provided very good protection, as the survival rate of the immunized neonatal mice was 100% after challenges with CV-A16 at a dose of 1000 LD50. Passive protective effects were transferred to the neonates via the mother, thus protecting all the pups against challenges with the homologous or heterologous strains of CV-A16 at a dose of 1000 LD50. In addition, intranasal immunization with CV-A16 VLPs also induced the production of mucosal secretory IgA (s-IgA) antibodies, which may inhibit CV-A16 virus invasion. This study provides valuable supplemental information to facilitate our understanding of the specific protective efficacy of CV-A16 VLPs and has significance for development of the candidate vaccine into a safe and effective vaccine.
XC and WX conceived and designed the study; XC performed the experiments; YZ performed the data analyses; NM performed the ELISPOT analyses; SZ and TJ performed the ELISAs and analysed and interpreted the data. The manuscript was written by XC and proofread by WX. All authors revised the manuscript and approved the final version.
This work was supported by the Beijing Natural Science Foundation (Grant no. 7184208), the National Science and Technology Major Project of the Ministry of Science and Technology of China (Grant nos. 2018ZX10201002-003-009, 2017ZX10104001-005-010, 2018ZX10713002, and 2018ZX10713001-003), the Basic and Clinical Research Cooperation Project of Capital Medical University (Grant no. 17JL11), and the Research Training Fund of Capital Medical University (Grant no. PYZ2017012). The sponsors played no role in the study design, data analysis, manuscript preparation, or decision to publish.
Compliance with ethical standards
Conflict of interest
The authors have no conflicts of interest to declare.
Animal and human rights statement
The program for immunization with CV-A16 VLPs or inactivated CV-A16 combined with CpG ODN was approved by the Ethical Committee of the National Institute of Viral Disease Control and Prevention, China CDC. The animal care and use protocol in this study abided by “The Guidance on Treating Experimental Animals”, which was promulgated by the Ministry of Science and Technology of China. No nonhuman primates were used in this study.
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